The Electrocardiographic Conundrum in a Patient on Methadone Maintenance Therapy and Cannabis Coingestion: A Case Report of a Heartbreaking Puzzle
Department of Internal Medicine, Conemaugh Health System, Johnstown, PA, USA
Department of Cardiology, Conemaugh Health System, Johnstown, PA, USA
Address for correspondence: Dr. Muhammad Adnan Zaman, Department of Internal Medicine, Conemaugh Health System, 1086 Franklin Street, Johnstown 15905, PA, USA. E-mail: mzaman@conemaugh.orgAbstract
Methadone is considered relatively safe when compared to other opioids. Methadone, however, can cause respiratory depression and QT prolongation. Among patients on methadone maintenance therapy, the rate of cannabis use is high. Multiple hypotheses, including the ‘exit hypothesis’ or ‘the cannabis association with reduced opioid use,’ need validation and further research. In this article, we present an interesting case of a 29-year-old female on methadone maintenance therapy for fifteen years who presented with methadone toxicity likely induced by systemic infection and cannabis co-ingestion. The patient had multiple cardiotoxic effects, including prolonged QT interval managed by antiarrhythmic medications, ST-segment elevation, and stress-induced cardiomyopathy managed conservatively. In this case report, the authors want to highlight the possible effects of methadone and cannabis co-injection, methadone toxicity induced by systemic infections, and increased awareness of these potentially catastrophic cardiotoxic effects in patients on high-dose methadone maintenance therapy.
INTRODUCTION
According to the Centers for Disease Control and Prevention, the age-adjusted rate of drug deaths involving methadone was one per every 100,000 standard population in 2022. Methadone is considered relatively safe when compared to natural and semisynthetic opioids, heroin, and other synthetic opioids. Methadone, however, can cause respiratory depression, QT prolongation, and augmented U waves. Among patients on methadone maintenance therapy, the rate of cannabis use is high. Multiple hypotheses, including the “exit hypothesis” or “cannabis association with reduced opioid use,” need validation and further research. On the other hand, there is always a concern about safety with coingestion of such drugs. In this article, we present an interesting case of a 29-year-old female on methadone maintenance therapy for 15 years who presented with methadone toxicity likely induced by systemic infection and cannabis coingestion.
CASE PRESENTATION
Initial presentation
A 29-year-old woman with a history of opioid use disorder was admitted to the emergency department after experiencing a tonic-clonic seizure. On arrival at the emergency department, the patient’s vitals were a temperature of 38.1°C, heart rate (HR) of 62 bpm, blood pressure of 114/73 mmHg, and oxygen saturation of 96% on a 15-l nonrebreather mask. She was intubated in the emergency department for her inability to protect her airway. The collateral history from family members revealed that the patient was on methadone for the last 14 years, with a recent stable dose of 135 mg of methadone daily. She was not feeling well, with nausea and vomiting for the previous 2–3 days, and started taking cannabis along with methadone. The patient reported taking 20–30 mg of cannabis tablets three to four times daily. Of note, the patient was taking this cannabis from the streets, and the exact strength of this cannabis extract might not be accurate.
Diagnostic workup
Initial emergency diagnostic laboratory workup revealed lactic acid of 14.6, potassium of 2.8, and sodium of 126. The detailed laboratory workup is also shown in Table 1. The urine drug screen was positive for cannabis, methadone, and benzodiazepines (benzodiazepines received prehospital for seizures). Computed tomography of the head was unremarkable for any acute intracranial pathology. Multifocal ground infiltrates were observed on the computed topography of the chest. Continuous electroencephalography revealed generalized epileptiform discharges predominantly in the right hemisphere. Initial echocardiography showed an ejection fraction of 25% with Grade 1 diastolic dysfunction, apical akinesis, and globally hypokinetic left ventricular wall [Video 1].
| Laboratory test | Reference value | Patient’s test results | Laboratory test | Reference value | Patient’s test results |
|---|---|---|---|---|---|
| White blood cell | 3.10–8.50×103/μL | 12.5 | B-HCG, qualitative | Negative | Negative |
| Red blood cell | 4.50–6.30×106/μL | 5.6 | BUN | 8–26 mg/dL | 16 |
| Hemoglobin | 14.0–18.0 g/dL | 15.7 | Creatinine | 0.70–1.30 mg/dL | 1.1 |
| Hematocrit | 40%–54% | 49 | Serum glucose | 83–110 mg/dL | 161 |
| Neutrophils | 38.0%–70.0% | 67 | Troponin I high sensitivity | 0.00–34.00 ng/L | 8.88 |
| Lymphocytes | 0.9–2.9×103/μL | 21 | Myoglobin | 0.0–106.0 ng/mL | 199.8 |
| Sodium | 136–145 mmol/L | 126 | Serum osmolality | 280–300 mOsm/kg | 284 |
| Potassium | 3.5–5.1 mmol/L | 2.8 | TSH | 0.35–4.94 uIU/mL | 4.65 |
| Chloride | 98–107 mmol/L | 79 | Cortisol AM | 5.27–22.45 ug/mL | 23.99 |
| Bicarbonate | 22–31 mEq/L | 28 | Lactate | 0.5–2.0 mmol/L | 14.6 |
| Calcium | 8.50–10.30 mg/dL | 8.6 | Brain natriuretic peptide | 0–100 pg/mL | 8 |
| Magnesium | 1.6–2.6 mg/dL | 3.0 | C-reactive protein | 0.0–0.8 mg/dL | 8.8 |
Electrocardiography-related changes
Three pertinent electrocardiograms (EKGs) are shown in Figures 1-3. Figure 1 (EKG at presentation) reveals ventricular bigeminy and a prolonged QT interval with ventricular ectopic occurring on the T wave, suggesting a high risk of inducing polymorphic ventricular tachycardia and torsades de pointes (TdP). Figure 2 (EKG at day 2) reveals diffuse prominent T waves inversion ‘roller coaster T waves and a prolonged corrected QT (QTc) interval of 734 milliseconds, calculated by Bazett method (HR 79 bpm). Figure 3 (EKG at day 3) shows a convex J point ST-segment elevation in II, III, aVF, V2–V6, T waves inversion in V3–V6, and possible minimal reciprocal changes in I and aVL.
Management
The patient was transferred to the critical care floor and was started on levetiracetam 1 g twice daily after the appropriate loading dose for seizures. She was empirically treated with ampicillin–sulbactam and vancomycin initially for pneumonia and later transitioned to ceftriaxone for positive respiratory cultures of streptococcus pneumoniae. She also received a 5-day course of oseltamivir for influenza infection during the same period. Electrolytes were continuously monitored throughout the admission. The only concerning dyselectrolytemia was potassium of 2.8 at presentation, which was adequately repleted and normalized within 10 h of hospital admission. It is pertinent to mention that despite potassium normalization, prolonged QTc interval persisted throughout the days, making it a less likely only cause for prolonged QTc interval. Considering the ST-segment elevation and minimal reciprocal changes, she underwent coronary computed tomography angiography, which revealed no visible stenosis or occlusion in coronary arteries.
The patient’s initial vitals revealed an HR of around 50–70 beats per min, with a nadir level reaching 40–50 beats per min at times. As a low HR is associated with worsening QT interval prolongation, this minimal bradycardia was also treated aggressively to keep an HR >80–90 bpm to offset the risk of TdP. For bradycardia associated with prolonged QT interval likely secondary to methadone and possibly exacerbated by multiple other analgesia-sedatives administered in critical care settings, she received dopamine and lidocaine infusion followed by oral mexiletine 150 mg three times a day. The patient also received continuous magnesium replacements to avoid the risk of TdP. The reduced ejection fraction, likely in the setting of stress-induced cardiomyopathy, was managed conservatively, and repeat echocardiography showed significant improvement in the ejection fraction [Video 1].
Follow-up
The patient remained intubated for 3 days and was discharged on day 6 of admission. After inpatient multidisciplinary team and outpatient methadone clinic team discussions, she was started on 70 mg of methadone (half of the original dose) after 6 days. She was sent home with a methadone slow up-titration plan and EKG monitoring. Six months postdischarge, EKG revealed normal sinus rhythm, QTc interval of 462 ms, and no ST-T wave changes.
DISCUSSION
Exacerbating factor: Is it cannabis, pneumonia, or both?
Respiratory depression is the most severe side effect in patients on methadone maintenance therapy because of its long half-life. Other than respiratory depression, prolonged QT interval, and augmented U waves lead to TdP and arrhythmias, central effects lead to somnolence, cognitive impairment, and seizures, and gastrointestinal symptoms include nausea and vomiting.[12] The incidence of cannabis use in patients with methadone maintenance therapy is high. A meta-analysis by Hallinan et al. revealed that cannabis may increase methadone clearance rather than enhancing toxicity.[3] Similar deductions were induced by Lake and St Pierre.[4] However, there are multiple small studies/case reports about the potential toxicity of methadone when coingested with cannabis. Cannabis inhibits cytochrome P450 (CYP) enzymes like CYP3A4 and CYP2C19, potentially contributing to methadone toxicity.[25] Along similar lines, a methadone dose of >100 mg per day is considered a high dose, and such patients are more prone to have methadone toxicity if they have underlying hepatic impairment or concurrent cannabis use.
On the other hand, pneumonia also exacerbates the respiratory deterioration in the setting of methadone toxicity. Systemic infections can lead to hepatic impairment during methadone metabolism. Flanagan et al. revealed pneumonia as one of those associated factors leading to methadone-related deaths in detention.[6] Despite minimal aspartate aminotransferase elevation of 63 U/L at initial presentation, no further workup for hepatic impairment was done as conservative management led to complete recovery of transaminitis.
Methadone-induced QT prolongation and augmented U waves
Methadone inhibits cardiac inward rectifier potassium current, leading to delayed repolarization and manifesting as increased U wave amplitude. Methadone also increases the prolonged QT interval by inhibiting the human ether-a-go-go-related gene.[7] U waves and QT interval prolongation are cardiac markers for assessing the risk of arrhythmias in such cases. The American College of Cardiology, American Heart Association, and Heart Rhythm Society recommend beta-blockers, magnesium and potassium replacement, and sodium channel blockers as effective strategies while simultaneously addressing the underlying cause to prevent progression to TdP.[8] Lidocaine, a class IB antiarrhythmic, also has a role in drug-induced QT interval prolongation. Another strategy is increasing the HR, which can decrease the QT interval, thereby reducing the likelihood of TdP. It is beneficial in cases with pause-dependent TdP or bradycardia.[910] Our patient’s HR was around 50–60 beats. Hence, she was started on dopamine with a target HR of >90 bpm. Isoproterenol and pacing are also effective in such cases.
Methadone-associated ST-segment elevation: myth or reality?
Sheibani et al. conducted a retrospective study involving 51 deceased intensive care unit-admitted patients. The study found that ST-T abnormalities, including ST elevation, were commonly present in 64.7% of the patients due to pure methadone toxicity, with a specific incidence of ST elevation particularly highlighted in methadone-naïve individuals.[11] Of note, there was no correlation between ST-T abnormalities and coronary disease in autopsy for all the individuals. While the literature is scarce about methadone as a possible cause for ST-segment elevation, ST-T abnormalities might be prevalent in methadone toxicity.[12] Although approximately 125,000 patients younger than 44 years old experience acute myocardial infarction every year, her ST-segment elevation was attributed to stress-induced cardiomyopathy and possible methadone toxicity rather than occlusive coronary artery disease, as evidenced by computed tomography angiography of the heart.
Cannabis induced effects
As most of the findings of methadone toxicity (respiratory depression, hepatotoxicity, coma, seizures etc.) can also be a manifestation of cannabis toxicity, at times, it is difficult to appreciate whether the manifestation is secondary to methadone, cannabis, or both. Interestingly, the EKG findings of cannabis toxicity also include ST elevation, particularly in V1 and V2 mimicking Brugada syndrome, and QT interval prolongation, underscoring significant cardiac risk associated with cannabis use.[131415]
CONCLUSION
Whether the coingestion of methadone and cannabis is a toxic duo for the heart remains elusive. Systemic infections worsen methadone toxicity. Patients on high-dose methadone should be consulted about potential methadone toxicity with associated illness, cannabis coingestion, or hepatic impairment. Patients on high-dose methadone should be considered for other options like buprenorphine, which has less QT-prolonging effect.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
There are no conflicts of interest.